In most aseptic pharmaceutical cleanrooms, the final step in removing airborne particles occurs in a high efficiency particulate air (HEPA) or ultra-low penetration air (ULPA) filter that is delivering air into a controlled space. Whether the cleanroom attains and maintains its designed cleanliness class depends largely on the performance of these filters. Hence, it is a common and good practice to test the performance of all filters installed in cleanrooms to ensure that they meet the designed specifications. Filters are typically tested at the time of manufacture for overall efficiency and leaks. However, in some cleanrooms within regulated industries, such as the pharmaceutical industry, these filters are also required to be certified periodically to ensure acceptable performance during their service life. Various organizations issue recommended practices for certification of HEPA and ULPA type filters for filter leak tests and guidelines for testing and classifying such filters.
In current HEPA air filtration micro-glass media, the standard utilized in the pharmaceutical industry in aseptic processing has serious problems due to the media being fragile resulting in damage from handling, pressure, overloading and the like. Such damage can result in leaks of the filtration media thereby compromising functionality. Leakage and damage of microglass filtration media within the pharmaceutical clean room environment is significant such that the U.S. Food and Drug Administration has issued guidelines ensuring filtration effectiveness of microglass HEPA filters by testing on a regular basis. Testing of such microglass HEPA filters in such aseptic environment is completed using high concentration oil based aerosols such as DOP (dioctylphthlate), PAO (poly-alpha olefin), DEHS (Di-Ethyl-Hexyl-Sebacat), and other similar compounds measured by traditional photometers capable of measuring such upstream and downstream concentrations. The aerosols used for such filter leak tests and challenging of these filters should meet specifications for critical physicochemical attributes such as viscosity. Leakage threshold rates of 0.01% or greater of upstream concentration from these compounds is typically the testing limit at which the pharmaceutical installation and processing area would either have to replace the filter or repair the same. The upstream concentration should always be measured at the start and end of testing.
The DOP/PAO method for aseptic pharmaceutical room filtration application and testing dates to the 1960's. Such testing of the filters in aseptic room filtration is required by regulation at least every 6-12 months by challenging the filtration media with a defined aerosol. The required aerosol challenge is maintained at a high concentration of about 20 μg PAO/L of air. A measurement of 15 μg of PAO/liter corresponds to about 20 grams of PAO/800 cfm filter/hour. For normal or standard microglass filtration media, a one-time oil based challenge compound may not negatively impact filter life of the media but may affect other structures of the filter. However, by testing at such concentrations on a regular basis, standard filter life including regular challenge testing can limit to less than five years the life cycle for microglass HEPA filtration.
In such standard challenging methodology for pharmaceutical applications and installs, a predefined challenging compound such as PAO is provided upstream of the filtration media in place. The PAO is injected into the airstream just prior to the in-situ media by nozzle or other known and calibrated device at such high concentration levels to properly determine filtration effectiveness. Such injection device creates a poly-dispersed aerosol composed of particles with light scattering mean droplet diameters in the submicron size range. A challenge concentration, as mentioned, is provided at up to about 20 μg/L which is continually introduced upstream of the filter for about three to four hours for proper certification. An upstream challenging port in the filter housing is utilized for photometric analysis. The filter face is scanned on the downstream side with the photometer probe and calculated as a percent of the upstream challenge. Scanning is conducted on the entire face of the filter to generate proper leakage analysis. Probe reading of about 0.01% as leak criteria would be indicative of a significant leak but requires, as seen, fairly high concentrations of upstream PAO which can have deleterious effects on the filtering media and HEPA performance.
Significant problems also arise in the use of PAO challenge compounds. Significant fouling of the filtration media may occur over a plurality of challenging cycles. Further, PAO has been shown to cause excessive oiling of the microglass filtering media which can result in bleed through of the challenge compound. Further, such excessive challenging can cause the filter media to become less efficient, exhibiting more of a pressure drop and correspondent higher energy costs. Additionally, the PAO challenge compound has been shown to cause damage to the filtering gel seals and gaskets resulting in potential leakage points. PAO may further cause liquification of silicon based gels or may harden or otherwise reduce the effectiveness of urethane based gel seals.
Alternative aseptic pharmaceutical filter designs have included the use of additional pre-filter requirements which work to protect the primary filtration media during normal air handling load and during challenging. Such pre-filters foul earlier in the filter life cycle thereby requiring periodic replacement and increased maintenance costs. Such pre-filtering is undesirable in that additional filtration media is therefore required, doubling of maintenance and handling requirements are expected and a lack of efficiency and increased pressure drop result.
Other problems associated with traditional micro-fiberglass HEPA filters are that they are a relatively fragile filter medium which do not react well to handling, in-place contact, vibration, humidity or chemical exposure. Such micro-fiberglass media may be readily damaged through normal handling and also have a reasonably short shelf life. Damage resulting from these various factors can cause leakage and unfiltered air to pass through the media. Further, the filter can fail normal challenging sequences as a result of such damage to the media. Thus, it is desirable to provide a filtering media that meets full HEPA filtration requirements, may be utilized in the aseptic pharmaceutical industry environment, and is more durable for handling and more reliable in remaining fully functional after required challenging sequences and during normal course of operations. However, when testing an ePTFE ULPA filter with 15 mg/m3 (μg/L) of PAO, a pressure drop increase of 96% occurred in approximately 5.25 hours at 650 cfm(2). The study clearly showed PAO exposure on the order of 15 mg/m3 (μg/L) was detrimental to ULPA ePTFE filters due to the drastic increase in the filter resistance (pressure drop) with time. This is due to the loading and occlusion of the pores in the ePTFE.
In addition to filter loading, when considering testing of ePTFE filters with the conventional use of PAO as a challenge aerosol, bleed through is also a potential issue. The issue of bleed through may occur when using thermally generated PAO to test ePTFE filters. This is due to the thermally generated aerosol having a 0.10-0.45 mass mean diameter which is closer to the MPPS of the filter. This creates an issue with a photometer measuring a concentration and looking for leaks at or above 0.01%. The bleed through could erroneously manifest itself as an artificially large leak or in some cases a continuous leak across the filter measuring a 0.025% or less leak rate.
It is therefore desirable to provide a fully functional HEPA filtration media which meets all requirements, is relatively durable, may be challenged appropriately to determine filtering effectiveness and leakage and which further meets all required aseptic filtration standards. It is further desirable to provide such filtration media without additional pre-filter requirements and with appropriate methodology to determine full functionality of the media and determine possible leakage points without causing fouling of the in-situ filters.
Thus, there is a need in the art to provide a fully functional aseptic pharmaceutical filter media which has associated full testing methodology, is durable, maintains HEPA filtration efficiencies and which has a long in-place filtration life.